tbuckley/cabot-search huggingface dataset:
Cytoplasmic-delivery of polyinosine-polycytidylic acid inhibits pancreatic cancer progression increasing survival by activating Stat1-CCL2-mediated immunity
Authors: Praveen Bhoopathi, Amit Kumar, Anjan K Pradhan, Santanu Maji, Padmanabhan Mannangatti, Jolene J Windle, Mark A Subler, Dongyu Zhang, Vignesh Vudatha, Jose G Trevino, Esha Madan, Azeddine Atfi, Devanand Sarkar, Rajan Gogna, Swadesh K Das, Luni Emdad, Paul B Fisher
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine–polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth. When pIC is delivered into the cytoplasm using polyethyleneimine (PEI), pIC-PEI, programmed-cell death is induced in PDAC. Transfection of [pIC] PEI into PDAC cells inhibits growth, promotes toxic autophagy and also induces apoptosis in vitro and in vivo in animal models. Methods The KPC transgenic mouse model that recapitulates PDAC development in patients was used to interrogate the role of an intact immune system in vivo in PDAC in response to [pIC] PEI . Antitumor efficacy and survival were monitored endpoints. Comprehensive analysis of the tumor microenvironment (TME) and immune cells, cytokines and chemokines in the spleen, and macrophage polarization were analyzed. Results Cytosolic delivery of [pIC] PEI induces apoptosis and provokes strong antitumor immunity in vivo in immune competent mice with PDAC. The mechanism underlying the immune stimulatory properties of [pIC] PEI involves Stat1 activation resulting in CCL2 and MMP13 stimulation thereby provoking macrophage polarization. [pIC] PEI induces apoptosis via the AKT-XIAP pathway, as well as macrophage differentiation and T-cell activation via the IFNγ-Stat1-CCL2 signaling pathways in PDAC. In transgenic tumor mouse models, [pIC] PEI promotes robust and profound antitumor activity implying that stimulating the immune system contributes to biological activity. The [pIC] PEI anti-PDAC effects are enhanced when used in combination with a standard of care (SOC) treatment, that is, gemcitabine. Conclusions In summary, [pIC] PEI treatment is non-toxic toward normal pancreatic cells while displaying strong cytotoxic and potent immune activating activities in PDAC, making it an attractive therapeutic when used alone or in conjunction with SOC therapeutic agents, potentially providing a safe and effective treatment protocol with translational potential for the effective therapy of PDAC.
Targeting myeloid checkpoint Siglec-10 reactivates antitumor immunity and improves anti-programmed cell death 1 efficacy in gastric cancer
Authors: Kunpeng Lv, Mengyao Sun, Hanji Fang, Jieti Wang, Chao Lin, Hao Liu, Heng Zhang, He Li, Hongyong He, Yun Gu, Ruochen Li, Fei Shao, Jiejie Xu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Objective Immunotherapy has not yielded satisfactory therapeutic responses in gastric cancer (GC). However, targeting myeloid checkpoints holds promise for expanding the potential of immunotherapy. This study aims to evaluate the critical role of Siglec-10 + tumor-associated macrophages (TAMs) in regulating antitumor immunity and to explore the potential of the myeloid checkpoint Siglec-10 as an interventional target. Design Siglec-10 + TAMs were assessed based on immunohistochemistry on tumor microarrays and RNA-sequencing data. Flow cytometry, RNA sequencing, and single-cell RNA-sequencing analysis were employed to characterize the phenotypic and transcriptional features of Siglec-10 + TAMs and their impact on CD8 + T cell-mediated antitumor immunity. The effectiveness of Siglec-10 blockade, either alone or in combination with anti-programmed cell death 1 (PD-1), was evaluated using an ex vivo GC tumor fragment platform based on fresh tumor tissues. Results Siglec-10 was predominantly expressed on TAMs in GC, and associated with tumor progression. In Zhongshan Hospital cohort, Siglec-10 + TAMs predicted unfavorable prognosis (n=446, p&lt;0.001) and resistance to adjuvant chemotherapy (n=331, p&lt;0.001), which were further validated in exogenous cohorts. In the Samsung Medical Center cohort, Siglec-10 + TAMs demonstrated inferior response to pembrolizumab in GC (n=45, p=0.008). Furthermore, Siglec-10 + TAMs exhibited an immunosuppressive phenotype and hindered T cell-mediated antitumor immune response. Finally, blocking Siglec-10 reinvigorated the antitumor immune response and synergistically enhances anti-PD-1 immunotherapy in an ex vivo GC tumor fragment platform. Conclusions In GC, the myeloid checkpoint Siglec-10 contributes to the regulation of immunosuppressive property of TAMs and promotes the depletion of CD8 + T cells, ultimately facilitating immune evasion. Targeting Siglec-10 represents a potential strategy for immunotherapy in GC.
When I use a word . . . Medicines regulation—apothecaries, quacks, chemists, druggists, pharmacists
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Many terms have been used to describe individuals whose main job involves the preparation and dispensing of medicines. These include apothecaries, quacks, chemists and druggists, and pharmacists. The definitions and uses of these different terms have not always been clear, but they do throw light on the ways in which medicines were prepared and dispensed over the years, and by whom, since physicians first sought to exert power over the apothecaries.
FDG PET/CT in Hantavirus Hemorrhagic Fever With Renal Syndrome
Authors: Yeon-Hee Han, Chang-Seop Lee
Journal: Clinical Nuclear Medicine (2023)

A 58-year-old man with fever, myalgia, and dysuria was admitted to the hospital. Because of prolonged fever, FDG PET/CT was performed. Surprisingly, bilateral kidneys were rapidly enlarged for 5 days with the renal parenchyma showing intense hypermetabolism. FDG PET/CT demonstrated physiology of Hantavirus invading kidneys and causing nephritis. This case illustrates that FDG PET/CT could be the choice of image modality for diagnosis and treatment evaluation of patients suspected of hemorrhagic fever with renal syndrome. To the best of our knowledge, this is the first report of FDG PET/CT image for a patient with hemorrhagic fever with renal syndrome.
Integrating Melt Electrowriting and Fused Deposition Modeling to Fabricate Hybrid Scaffolds Supportive of Accelerated Bone Regeneration
Authors: Kian F. Eichholz, Pierluca Pitacco, Ross Burdis, Farhad Chariyev‐Prinz, Xavier Barceló, Brooke Tornifoglio, Ryan Paetzold, Orquidea Garcia, Daniel J Kelly
Journal: Advanced Healthcare Materials (2023)

Emerging additive manufacturing (AM) strategies can enable the engineering of hierarchal scaffold structures for guiding tissue regeneration. Here, the advantages of two AM approaches, melt electrowriting (MEW) and fused deposition modelling (FDM), are leveraged and integrated to fabricate hybrid scaffolds for large bone defect healing. MEW is used to fabricate a microfibrous core to guide bone healing, while FDM is used to fabricate a stiff outer shell for mechanical support, with constructs being coated with pro-osteogenic calcium phosphate (CaP) nano-needles. Compared to MEW scaffolds alone, hybrid scaffolds prevent soft tissue collapse into the defect region and support increased vascularization and higher levels of new bone formation 12 weeks post-implantation. In an additional group, hybrid scaffolds are also functionalized with BMP2 via binding to the CaP coating, which further accelerates healing and facilitates the complete bridging of defects after 12 weeks. Histological analyses demonstrate that such scaffolds support the formation of well-defined annular bone, with an open medullary cavity, smooth periosteal surface, and no evidence of abnormal ectopic bone formation. These results demonstrate the potential of integrating different AM approaches for the development of regenerative biomaterials, and in particular, demonstrate the enhanced bone healing outcomes possible with hybrid MEW-FDM constructs.
Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM)
Authors: Naveen S. Vasudev, Gemma Ainsworth, Sarah Brown, Lisa Pickering, Tom Waddell, Kate Fife, Richard Griffiths, Anand Sharma, Eszter Katona, Helen Howard, Galina Velikova, Anthony Maraveyas, Janet Brown, Carmel Pezaro, Mark Tuthill, Ekaterini Boleti, Amit Bahl, Bernadett Szabados, Rosamonde E. Banks, Joanne Brown, Balaji Venugopal, Poulam Patel, Ankit Jain, Stefan N. Symeonides, Paul Nathan, Fiona J. Collinson, Thomas Powles
Journal: Journal of Clinical Oncology (2023)

PURPOSE Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.
Automated fabrication of a scalable heart-on-a-chip device by 3D printing of thermoplastic elastomer nanocomposite and hot embossing
Authors: Qinghua Wu, Ruikang Xue, Yimu Zhao, Kaitlyn Ramsay, Erika Yan Wang, Houman Savoji, Teodor Veres, Sarah H. Cartmell, Milica Radisic
Journal: Bioactive Materials (2023)

The successful translation of organ-on-a-chip devices requires the development of an automated workflow for device fabrication, which is challenged by the need for precise deposition of multiple classes of materials in micro-meter scaled configurations. Many current heart-on-a-chip devices are produced manually, requiring the expertise and dexterity of skilled operators. Here, we devised an automated and scalable fabrication method to engineer a Biowire II multiwell platform to generate human iPSC-derived cardiac tissues. This high-throughput heart-on-a-chip platform incorporated fluorescent nanocomposite microwires as force sensors, produced from quantum dots and thermoplastic elastomer, and 3D printed on top of a polystyrene tissue culture base patterned by hot embossing. An array of
Engineering materials for pyroptosis induction in cancer treatment
Authors: Jiayi Liu, Taili Chen, XianLing Liu, ZhiHong Li, Yong Zhang
Journal: Bioactive Materials (2023)

Cancer remains a significant global health concern, necessitating the development of innovative therapeutic strategies. This research paper aims to investigate the role of pyroptosis induction in cancer treatment. Pyroptosis, a form of programmed cell death characterized by the release of pro-inflammatory cytokines and the formation of plasma membrane pores, has gained significant attention as a potential target for cancer therapy. The objective of this study is to provide a comprehensive overview of the current understanding of pyroptosis and its role in cancer treatment. The paper discusses the concept of pyroptosis and its relationship with other forms of cell death, such as apoptosis and necroptosis. It explores the role of pyroptosis in immune activation and its potential for combination therapy. The study also reviews the use of natural, biological, chemical, and multifunctional composite materials for pyroptosis induction in cancer cells. The molecular mechanisms underlying pyroptosis induction by these materials are discussed, along with their advantages and challenges in cancer treatment. The findings of this study highlight the potential of pyroptosis induction as a novel therapeutic strategy in cancer treatment and provide insights into the different materials and mechanisms involved in pyroptosis induction.
Flashback Foreword: Bevacizumab and Irinotecan in Recurrent Glioblastoma
Authors: Ingo K. Mellinghoff
Journal: Journal of Clinical Oncology (2023)

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma. November 07, 2023 ARTICLE CITATION DOI: 10.1200/JCO.23.01865 Journal of Clinical Oncology - published online before print November 7, 2023 PMID: 37935102 Flashback Foreword: Bevacizumab and Irinotecan in Recurrent Glioblastoma Ingo K. Mellinghoff , MD1,2xIngo K. MellinghoffSearch for articles by this author Show More 1Former Associate Editor, Journal of Clinical Oncology, Alexandria, VA2Department of Neurology, Memorial Sloan Kettering Cancer Center, New York City, NY https://doi.org/10.1200/JCO.23.01865 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 2009, Friedman et al1 reported the activity of bevacizumab in the treatment of recurrent glioblastoma. Although the initial enthusiasm regarding the use of bevacizumab in glioblastoma has faded over the years, because of its lack of effect on overall survival, the Friedman et al1 trial remains a milestone in the quest for molecularly targeted therapies for glioblastoma. Companion Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Authors: Henry S. Friedman, Michael D. Prados, Patrick Y. Wen, Tom Mikkelsen, David Schiff, Lauren E. Abrey, W.K. Alfred Yung, Nina Paleologos, Martin K. Nicholas, Randy Jensen, James Vredenburgh, Jane Huang, Maoxia Zheng, Timothy Cloughesy
Journal: Journal of Clinical Oncology (2023)

We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.
Biocompatible Rhamnolipid Self‐Assemblies with pH‐Responsive Antimicrobial Activity
Authors: Parth Kadakia, Jules D. P. Valentin, Linda Hong, Samuel Watts, Owais Abdul Hameed, Michael Walch, Stefan Salentinig
Journal: Advanced Healthcare Materials (2023)

Abstract There is an urgent need for alternative antimicrobial materials due to the growing challenge of bacteria becoming resistant to conventional antibiotics. This study demonstrates the creation of a biocompatible pH‐switchable antimicrobial material by combining bacteria‐derived rhamnolipids (RL) and food‐grade glycerol monooleate (GMO). The integration of RL into dispersed GMO particles, with an inverse‐type liquid crystalline cubic structure in the core, leads to colloidally stable supramolecular materials. The composition and pH‐triggered structural transformations are studied with small‐angle X‐ray scattering, cryogenic transmission electron microscopy, and dynamic light scattering. The composition‐structure‐activity relationship is analyzed and optimized to target bacteria at acidic pH values of acute wounds. The new RL/GMO dispersions reduce Staphylococcus aureus (S. aureus) populations by 7‐log after 24 h of treatment with 64 µg mL −1 of RL and prevent biofilm formation at pH = 5.0, but have no activity at pH = 7.0. Additionally, the system is active against methicillin‐resistant S. aureus (MRSA) with minimum inhibitory concentration of 128 µg mL −1 at pH 5.0. No activity is found against several Gram‐negative bacteria at pH 5.0 and 7.0. The results provide a fundamental understanding of lipid self‐assembly and the design of lipid‐based biomaterials, which can further guide the development of alternative bio‐based solutions to combat bacteria.
Laparoscopy-assisted trans-hiatal endoscopic removal of an intragastric balloon after placement-related esophageal perforation
Authors: Pablo Cortegoso Valdivia, Giorgio Dalmonte, Marina Valente, Lucia Ballabeni, Federica Gaiani, Gian Luigi de' Angelis, Federico Marchesi
Journal: Endoscopy (2023)

Intragastric balloon placement is a minimally invasive endoscopic procedure for the treatment of obesity [1] [2]. Severe adverse events such as gastric perforation, migration, and intestinal obstruction, albeit rare, may occur [3] [4]; esophageal perforation due to balloon insertion has been reported in only a handful of cases [5].
Endoscopic intermuscular dissection of a residual rectal neuroendocrine tumor with high-pressure injection and double-clip traction
Authors: Marion Schaefer, Jérémie Albouys, Sophie Geyl, Romain Legros, Timothée Wallenhorst, Mathieu Pioche, Jérémie Jacques
Journal: Endoscopy (2023)

Endoscopic resection, with advanced techniques such as modified endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), is the first-line treatment for small grade 1 rectal neuroendocrine tumors (NETs), and complete histological resection is mandatory to avoid overtreatment or unnecessary follow-up [1]. Rectal NETs are rare tumors that can be misdiagnosed and consequently inadequately resected with cold snare, hot snare polypectomy, or biopsy forceps, leading to incomplete resection [2]. In such cases, complementary resection using ESD or transanal endoscopic microsurgery can be proposed to achieve complete resection and dispense with further follow-up [3]. Recently, endoscopic intermuscular dissection has been described to increase the deep resection margin for invasive submucosal rectal cancer [4].
Time to treat the climate and nature crisis as one indivisible global health emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: Cardiovascular Research (2023)
Differences in treatment of stage I colorectal cancers: a population-based study of colorectal cancers detected within and outside of a screening program
Authors: Esther Toes-Zoutendijk, Emilie C. H. Breekveldt, Lisa van der Schee, Iris D. Nagtegaal, Marloes A. G. Elferink, Iris Lansdorp-Vogelaar, Leon M. G. Moons, Monique E. van Leerdam
Journal: Endoscopy (2023)

Screen-detected colorectal cancers (CRCs) are often treated less invasively than stage-matched non-screen-detected CRCs, but the reasons for this are not fully understood. This study evaluated the treatment of stage I CRCs detected within and outside of the screening program in the Netherlands. METHODS : Data from the Netherlands Cancer Registry for all stage I CRCs diagnosed between January 1, 2008 and December 31, 2020 were analyzed, comparing patient, tumor, and treatment characteristics of screen-detected and non-screen-detected stage I CRCs. Multivariable logistic regression was used to assess the association between treatment (local excision only vs. surgical oncologic resection) and patient and tumor characteristics, stratified for T stage and tumor location. Screen-detected stage I CRCs were relatively more often T1 than T2 compared with non-screen-detected stage I CRCs (66.9 % vs. 53.3 %; P < 0.001). When only T1 tumors were considered, both screen-detected colon and rectal cancers were more often treated with local excision only than non-screen-detected T1 cancers (odds ratio [OR] 2.19, 95 %CI 1.93-2.49; and OR 1.29, 95 %CI 1.05-1.59, respectively), adjusted for sex, tumor location, lymphovascular invasion (LVI) status, and tumor differentiation. CONCLUSIONS : Less invasive treatment of screen-detected stage I CRC is partly explained by the higher rate of T1 cancers compared with non-screen-detected stage I CRCs. T1 stage I screen-detected CRCs were also more likely to undergo less invasive treatment than non-screen-detected CRCs, adjusted for risk factors such as LVI and tumor differentiation. Future research should investigate whether the choice of local excision was related to unidentified cancer-related factors or the expertise of the endoscopists.
Early detection of hepatocellular carcinoma via no end-repair enzymatic methylation sequencing of cell-free DNA and pre-trained neural network
Authors: Zhenzhong Deng, Yongkun Ji, Bing Han, Zhongming Tan, Yuqi Ren, Jinghan Gao, Nan Chen, Cong Ma, Yichi Zhang, Yunhai Yao, Hong Lu, Heqing Huang, Midie Xu, Lei Chen, Leizhen Zheng, Jianchun Gu, Deyi Xiong, Jianxin Zhao, Jinyang Gu, Zutao Chen, Ke Wang
Journal: Genome Medicine (2023)

Abstract Background Early detection of hepatocellular carcinoma (HCC) is important in order to improve patient prognosis and survival rate. Methylation sequencing combined with neural networks to identify cell-free DNA (cfDNA) carrying aberrant methylation offers an appealing and non-invasive approach for HCC detection. However, some limitations exist in traditional methylation detection technologies and models, which may impede their performance in the read-level detection of HCC. Methods We developed a low DNA damage and high-fidelity methylation detection method called No End-repair Enzymatic Methyl-seq (NEEM-seq). We further developed a read-level neural detection model called DeepTrace that can better identify HCC-derived sequencing reads through a pre-trained and fine-tuned neural network. After pre-training on 11 million reads from NEEM-seq, DeepTrace was fine-tuned using 1.2 million HCC-derived reads from tumor tissue DNA after noise reduction, and 2.7 million non-tumor reads from non-tumor cfDNA. We validated the model using data from 130 individuals with cfDNA whole-genome NEEM-seq at around 1.6X depth. Results NEEM-seq overcomes the drawbacks of traditional enzymatic methylation sequencing methods by avoiding the introduction of unmethylation errors in cfDNA. DeepTrace outperformed other models in identifying HCC-derived reads and detecting HCC individuals. Based on the whole-genome NEEM-seq data of cfDNA, our model showed high accuracy of 96.2%, sensitivity of 93.6%, and specificity of 98.5% in the validation cohort consisting of 62 HCC patients, 48 liver disease patients, and 20 healthy individuals. In the early stage of HCC (BCLC 0/A and TNM I), the sensitivity of DeepTrace was 89.6 and 89.5% respectively, outperforming Alpha Fetoprotein (AFP) which showed much lower sensitivity in both BCLC 0/A (50.5%) and TNM I (44.7%). Conclusions By combining high-fidelity methylation data from NEEM-seq with the DeepTrace model, our method has great potential for HCC early detection with high sensitivity and specificity, making it potentially suitable for clinical applications. DeepTrace: https://github.com/Bamrock/DeepTrace